scholarly journals Anti-COVID-19 Effects of Ten Structurally Different Hydrolysable Tannins through Binding with the Catalytic-Closed Sites of COVID-19 Main Protease: An In-Silico Approach

2020 ◽  
Author(s):  
Ibrahim Khalifa ◽  
Wei Zhu ◽  
Mohamed S. Nafie ◽  
Kunal Dutta ◽  
Chunmei Li
Keyword(s):  
Small Molecules ◽  
Operating Environment ◽  
Receptor Binding Site ◽  
Theoretical Approaches ◽  
Protease Enzyme ◽  
Main Protease ◽  
Hydrolysable Tannins ◽  
Therapeutic Compounds ◽  
Catalytic Dyad ◽  
Drug Discovery Target

Coronavirus disease 2019 (COVID-19) was recently raised and starting from China to all over the world. The viral main protease (3-chymotrypsin-like cysteine enzyme) controls COVID-19 duplication and manages its life cycle, making it a drug discovery target. Therefore, herein, we analyzed the theoretical approaches of 10 structurally different hydrolysable tannins as natural anti-COVID-19 through binding with the main protease of 2019-nCoV using molecular docking modelling via Molecular Operating Environment (MOE v2009) software. Our results revealed that there are top three hits may serve as potential anti-COVID-19 lead molecules for further optimization and drug development to control COVID-19. Pedunculagin, tercatain, and punicalin were found to faithfully interact with the receptor binding site and catalytic dyad (Cys145 and His41) of COVID-19 main protease, showing their successfully inhibit the protease enzyme of 2019-nCoV. We anticipated that this study would pave way for tannins based novel small molecules as more efficacious and selective anti-COVID-19 therapeutic compounds.

Identification of Main Protease of Coronavirus SARS-CoV-2 (Mpro)Inhibitors from Melissa officinalis

2020 ◽  
Vol 17 ◽  
Author(s):  
Olusola O. Elekofehinti ◽  
Opeyemi Iwaloye ◽  
Courage D. Famusiwa ◽  
Olanrewaju Akinseye ◽  
Joao B. T. Rocha
Keyword(s):  
Qsar Model ◽  
Computational Approach ◽  
Melissa Officinalis ◽  
Lead Compounds ◽  
Main Protease ◽  
The World ◽  
Recent Outbreak ◽  
Global Concern ◽  
Catalytic Dyad ◽  
Potential Therapeutic Intervention

Background: he recent outbreak of Coronavirus SARS-CoV-2 (Covid-19) which has rapidly spread around the world in about three months with tens of thousands of deaths recorded so far is a global concern. An urgent need for potential therapeutic intervention is of necessity. Mpro is an attractive druggable target for the development of anti-COVID-19 drug development. Compounds previously characterized from Melissa officinalis were queried against main protease of coronavirus SARS-CoV-2 using computational approach. Results: Melitric acid A and salvanolic acid A had higher affinity than lopinavir and ivermectin using both AutodockVina and XP docking algorithms. The computational approach was employed in the generation of QSAR model using automated QSAR, and in the docking of ligands from Melissa officinalis with SARS-CoV-2 Mpro inhibitors. The best model obtained was KPLS_Radial_28 (R2 = 0.8548 and Q2=0.6474, and was used in predicting the bioactivity of the lead compounds. Molecular mechanics based MM-GBSA confirmed salvanolic acid A as the compound with the highest free energy and predicted bioactivity of 4.777; it interacted with His-41 of the catalytic dyad (Cys145-His41) of SARS-CoV-2 main protease (Mpro), as this may hinder the cutting of inactive viral protein into active ones capable of replication. Conclusion: Salvanolic acid A can be further evaluated as potential Mpro inhibitor.

scholarly journals GRL-0920, an Indole Chloropyridinyl Ester, Completely Blocks SARS-CoV-2 Infection

mBio ◽  
2020 ◽  
Vol 11 (4) ◽  
Author(s):  
Shin-ichiro Hattori ◽  
Nobuyo Higshi-Kuwata ◽  
Jakka Raghavaiah ◽  
Debananda Das ◽  
Haydar Bulut ◽  
...  
Keyword(s):  
High Performance ◽  
Cytopathic Effect ◽  
Structural Modeling ◽  
Covalent Bonding ◽  
Liquid Chromatography Mass Spectrometry ◽  
Viral Breakthrough ◽  
Main Protease ◽  
Significant Toxicity ◽  
Catalytic Dyad ◽  
Shed Light

ABSTRACT We assessed various newly generated compounds that target the main protease (Mpro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and various previously known compounds reportedly active against SARS-CoV-2, employing RNA quantitative PCR (RNA-qPCR), cytopathicity assays, and immunocytochemistry. Here, we show that two indole-chloropyridinyl-ester derivatives, GRL-0820 and GRL-0920, exerted potent activity against SARS-CoV-2 in cell-based assays performed using VeroE6 cells and TMPRSS2-overexpressing VeroE6 cells. While GRL-0820 and the nucleotide analog remdesivir blocked SARS-CoV-2 infection, viral breakthrough occurred. No significant anti-SARS-CoV-2 activity was found for several compounds reportedly active against SARS-CoV-2 such as lopinavir, nelfinavir, nitazoxanide, favipiravir, and hydroxychroloquine. In contrast, GRL-0920 exerted potent activity against SARS-CoV-2 (50% effective concentration [EC50] = 2.8 μM) and dramatically reduced the infectivity, replication, and cytopathic effect of SARS-CoV-2 without significant toxicity as examined with immunocytochemistry. Structural modeling shows that indole and chloropyridinyl of the derivatives interact with two catalytic dyad residues of Mpro, Cys145 and His41, resulting in covalent bonding, which was verified using high-performance liquid chromatography–mass spectrometry (HPLC/MS), suggesting that the indole moiety is critical for the anti-SARS-CoV-2 activity of the derivatives. GRL-0920 might serve as a potential therapeutic for coronavirus disease 2019 (COVID-19) and might be optimized to generate more-potent anti-SARS-CoV-2 compounds. IMPORTANCE Targeting the main protease (Mpro) of SARS-CoV-2, we identified two indole-chloropyridinyl-ester derivatives, GRL-0820 and GRL-0920, active against SARS-CoV-2, employing RNA-qPCR and immunocytochemistry and show that the two compounds exerted potent activity against SARS-CoV-2. While GRL-0820 and remdesivir blocked SARS-CoV-2 infection, viral breakthrough occurred as examined with immunocytochemistry. In contrast, GRL-0920 completely blocked the infectivity and cytopathic effect of SARS-CoV-2 without significant toxicity. Structural modeling showed that indole and chloropyridinyl of the derivatives interacted with two catalytic dyad residues of Mpro, Cys145 and His41, resulting in covalent bonding, which was verified using HPLC/MS. The present data should shed light on the development of therapeutics for COVID-19, and optimization of GRL-0920 based on the present data is essential to develop more-potent anti-SARS-CoV-2 compounds for treating COVID-19.

scholarly journals Potential Binding Efficiency of Antiviral Drug Lopinavir Targeted to the Catalytic Dyad, His41 - Cys145 of SARS CoV -2 Main Protease

2020 ◽  
Author(s):  
Muthu Raj S ◽  
Manohar M ◽  
Mohan M ◽  
Ganesh P ◽  
Marimuthu K
Keyword(s):  
Antiviral Drug ◽  
Emergency Situation ◽  
Viral Disease ◽  
New Drugs ◽  
Viral Population ◽  
Protease Inhibition ◽  
Main Protease ◽  
Model Drug ◽  
Approved Drugs ◽  
Catalytic Dyad

<p>The spread of SARS CoV 2 across the globe rushed the scientific community to find out the potential inhibitor for controlling the viral disease. The main protease (Mpro) or Chymotrypsin protease (3CLpro) is involved in the cleavage of polyproteins, duplication of intracellular materials and release of nonstructural proteins. Cys-His catalytic dyad is located in the SARS-CoV Mpro which is the substrate-binding site located in domains I and II. There are many approved drugs that have their active protease inhibition capability. The targeting of the active site of the main protease is the better option to fight against the viral population. Lopinavir, ritonavir, Remdesivir and Chloroquine are some of the drug candidates considered to be involved in the treatment of SARS CoV 2 under emergency situation as a trial basis. In the present investigation we used lopinavir as a drug to bind the catalytic dyad His41, Cys145 of main protease. The minimum binding of energy of -11.45 kcal/mol observed with the binding of Cys145 and -10.93 kcal/mol was noted with the residue His41. The inhibition constant was also found to be relevant to the binding efficiency of the drug. This is considered to be a model drug target which is initiating the finding of many new drugs to target the current outbreak created by the virus SARS.CoV - 2.</p>

scholarly journals Crystal structure of SARS-CoV-2 main protease in complex with a Chinese herb inhibitor shikonin

2020 ◽  
Author(s):  
Jian Li ◽  
Xuelan Zhou ◽  
Yan Zhang ◽  
Fanglin Zhong ◽  
Cheng Lin ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Conformational Changes ◽  
Drug Targets ◽  
Chinese Herb ◽  
Binding Modes ◽  
High Potency ◽  
Main Protease ◽  
Covalent Inhibitors ◽  
Catalytic Dyad ◽  
Important Drug

AbstractMain protease (Mpro, also known as 3CLpro) has a major role in the replication of coronavirus life cycle and is one of the most important drug targets for anticoronavirus agents. Here we report the crystal structure of main protease of SARS-CoV-2 bound to a previously identified Chinese herb inhibitor shikonin at 2.45 angstrom resolution. Although the structure revealed here shares similar overall structure with other published structures, there are several key differences which highlight potential features that could be exploited. The catalytic dyad His41-Cys145 undergoes dramatic conformational changes, and the structure reveals an unusual arrangement of oxyanion loop stabilized by the substrate. Binding to shikonin and binding of covalent inhibitors show different binding modes, suggesting a diversity in inhibitor binding. As we learn more about different binding modes and their structure-function relationships, it is probable that we can design more effective and specific drugs with high potency that can serve as effect SARS-CoV-2 anti-viral agents.

scholarly journals Identification of inhibitors of SARS-CoV-2 3CL-Pro enzymatic activity using a small molecule in-vitro repurposing screen

2020 ◽  
Author(s):  
Maria Kuzikov ◽  
Elisa Costanzi ◽  
Jeanette Reinshagen ◽  
Francesca Esposito ◽  
Laura Vangeel ◽  
...  
Keyword(s):  
Enzymatic Activity ◽  
Small Molecules ◽  
Drug Target ◽  
Treatment Options ◽  
Cleavage Sites ◽  
X Ray ◽  
Binding Characteristics ◽  
Main Protease ◽  
Ic50 Values

Compound repurposing is an important strategy for the identification of effective treatment options against SARS-CoV-2 infection and COVID-19 disease. In this regard, SARS-CoV-2 main protease (3CL-Pro), also termed M-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyproteins pp1a and pp1ab at multiple distinct cleavage sites. We here report the results of a repurposing program involving 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and small molecules regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro, and have identified 62 additional compounds with IC50 values below 1 uM and profiled their selectivity towards Chymotrypsin and 3CL-Pro from the MERS virus. A subset of 8 inhibitors showed anti-cytopathic effect in a Vero-E6 cell line and the compounds thioguanosine and MG-132 were analysed for their predicted binding characteristics to SARS-CoV-2 3CL-Pro. The X-ray crystal structure of the complex of myricetin and SARS-Cov-2 3CL-Pro was solved at a resolution of 1.77 Angs., showing that myricetin is covalently bound to the catalytic Cys145 and therefore inhibiting its enzymatic activity.

Understanding small-molecule electro-oxidation on palladium based compounds – a feature on experimental and theoretical approaches

2018 ◽  
Vol 47 (24) ◽  
pp. 7864-7869 ◽  
Author(s):  
Saurav Ch. Sarma ◽  
Sebastian C. Peter
Keyword(s):  
Fuel Cells ◽  
Formic Acid ◽  
Small Molecules ◽  
Electrochemical Oxidation ◽  
Small Molecule ◽  
Energy Production ◽  
Green Energy ◽  
Theoretical Approaches ◽  
Electro Oxidation

Electrochemical oxidation of small molecules such as ethanol, methanol and formic acid on Pd based compounds has a great impact on green energy production in fuel cells.

scholarly journals High Throughput Virtual Screening to Discover Inhibitors of the Main Protease of the Coronavirus SARS-CoV-2

Molecules ◽  
2020 ◽  
Vol 25 (14) ◽  
pp. 3193 ◽  
Author(s):  
Olujide O. Olubiyi ◽  
Maryam Olagunju ◽  
Monika Keutmann ◽  
Jennifer Loschwitz ◽  
Birgit Strodel
Keyword(s):  
Natural Products ◽  
Kinase Inhibitors ◽  
Amino Acid Residues ◽  
Enzyme Dynamics ◽  
Hydrogen Bond Formation ◽  
Protease Enzyme ◽  
Main Protease ◽  
Starting Point ◽  
Approved Drugs

We use state-of-the-art computer-aided drug design (CADD) techniques to identify prospective inhibitors of the main protease enzyme, 3CLpro of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing COVID-19. From our screening of over one million compounds including approved drugs, investigational drugs, natural products, and organic compounds, and a rescreening protocol incorporating enzyme dynamics via ensemble docking, we have been able to identify a range of prospective 3CLpro inhibitors. Importantly, some of the identified compounds had previously been reported to exhibit inhibitory activities against the 3CLpro enzyme of the closely related SARS-CoV virus. The top-ranking compounds are characterized by the presence of multiple bi- and monocyclic rings, many of them being heterocycles and aromatic, which are flexibly linked allowing the ligands to adapt to the geometry of the 3CLpro substrate site and involve a high amount of functional groups enabling hydrogen bond formation with surrounding amino acid residues, including the catalytic dyad residues H41 and C145. Among the top binding compounds we identified several tyrosine kinase inhibitors, which include a bioflavonoid, the group of natural products that binds best to 3CLpro. Another class of compounds that decently binds to the SARS-CoV-2 main protease are steroid hormones, which thus may be endogenous inhibitors and might provide an explanation for the age-dependent severity of COVID-19. Many of the compounds identified by our work show a considerably stronger binding than found for reference compounds with in vitro demonstrated 3CLpro inhibition and anticoronavirus activity. The compounds determined in this work thus represent a good starting point for the design of inhibitors of SARS-CoV-2 replication.

scholarly journals In silico analysis and identification of promising hits against 2019 novel coronavirus 3C-like main protease enzyme

2020 ◽  
pp. 1-14 ◽  
Author(s):  
Shilpa Chatterjee ◽  
Arindam Maity ◽  
Suchana Chowdhury ◽  
Md Ataul Islam ◽  
Ravi K. Muttinini ◽  
...  
Keyword(s):  
In Silico ◽  
In Silico Analysis ◽  
Protease Enzyme ◽  
Main Protease ◽  
Novel Coronavirus ◽  
Silico Analysis

scholarly journals Identification of Potent Inhibitors of COVID-19 Main Protease Enzyme by Molecular Docking Study

2020 ◽  
Author(s):  
pooja singh ◽  
Angkita Sharma ◽  
Shoma Paul Nandi
Keyword(s):  
Molecular Docking ◽  
Antiviral Drug ◽  
Cyclopiazonic Acid ◽  
Docking Study ◽  
Molecular Docking Study ◽  
Docking Score ◽  
Protease Enzyme ◽  
Main Protease

<p>Within the span of a few months, the severe acute respiratory syndrome coronavirus, COVID-19 (SARS-CoV-2), has proven to be a pandemic, affecting the world at an exponential rate. It is extremely pathogenic and causes communicable infection in humans. Viral infection causes difficulties in breathing, sore throat, cough, high fever, muscle pain, diarrhea, dyspnea, and may lead to death. Finding a proper drug and vaccines against this virus is the need of the hour. The RNA genome of COVID19 codes for the main protease M<sup>pro</sup>, which is required for viral multiplication. To identify possible antiviral drug(s), we performed molecular docking studies. Our screen identified ten biomolecules naturally present in <i>Aspergillus flavus</i> and <i>Aspergillus oryzae</i> fungi. These molecules include Aspirochlorine, Aflatoxin B1, Alpha-Cyclopiazonic acid, Sporogen, Asperfuran, Aspergillomarasmine A, Maltoryzine, Kojic acid, Aflatrem and Ethyl 3-nitropropionic acid, arranged in the descending order of their docking score. Aspirochlorine exhibited the docking score of – 7.18 Kcal/mole, higher than presently used drug Chloroquine (-6.2930522 Kcal/mol) and out of ten ligands studied four has docking score higher than chloroquine. These natural bioactive compounds could be tested for their ability to inhibit viral growth <i>in- vitro</i> and <i>in-vivo</i>.<b> </b></p>

scholarly journals MOLECULAR DOCKING STUDY TO IDENTIFY POTENTIAL INHIBITOR OF COVID-19 MAIN PROTEASE ENZYME: AN IN-SILICO APPROACH

2020 ◽  
Author(s):  
Anurag Agrawal ◽  
Nem Kumar Jain ◽  
Neeraj Kumar ◽  
Giriraj T Kulkarni
Keyword(s):  
Molecular Docking ◽  
Active Site ◽  
Docking Study ◽  
Molecular Docking Study ◽  
Potential Threat ◽  
Discovery Studio ◽  
Chemical Structures ◽  
Potential Inhibitor ◽  
Protease Enzyme ◽  
Main Protease

This study belongs to identification of suitable COVID-19 inhibitors<br><div><br></div><div>Coronavirus became pandemic very soon and is a potential threat to human lives across the globe. No approved drug is currently available therefore an urgent need has been developed for any antiviral therapy for COVID-19. For the molecular docking study, ten herbal molecules have been included in the current study. The three-dimensional chemical structures of molecules were prepared through ChemSketch 2015 freeware. Molecular docking study was performed using AutoDock 4.2 simulator and Discovery studio 4.5 was employed to predict the active site of target enzyme. Result indicated that all-natural molecules found in the active site of enzyme after molecular docking. Oxyacanthine and Hypericin (-10.990 and -9.05 and kcal/mol respectively) have shown good binding efficacy among others but Oxyacanthine was the only natural product which made some of necessary interactions with residues in the enzyme require for target inhibition. Therefore Oxyacanthine may be considered to be potential inhibitor of main protease enzyme of virus but need to be explored for further drug development process. <br></div>

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